Bosentan, represented by structural formula (i) and chemically named 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzene-sulfonamide is an endothelin receptor antagonist. It is used for the treatment of disorders which are associated with endothelin activities, in particular circulatory and cardiovascular disorders such as hypertension, ischemia, pulmonary hypertension, vasospasm and angina pectoris. The marketed product comprising bosentan, Tracleer®, is indicated for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with grade III functional status.

Bosentan was first described in U.S. Pat. No. 5,292,740. The preparation method involves two steps (as shown in Scheme 1) starting from the dichloro compound, 4,6-dichloro-5-(o-methoxyphenoxy)-2,2′-bipyrimidine (1). The second reaction step is carried out in ethylene glycol with sodium metal used as the base at a temperature of 100-110° C.

One of the disadvantages of this process is the formation of an undesired ethylene glycol bis-sulfonamide dimer having formula (ii) in which two molecules of the pyrimidine monohalide molecule are coupled with one molecule of ethylene glycol. The removal of this impurity requires costly and laborious separation steps. To minimize the formation of this impurity a large excess of ethylene glycol is used. However, using a large excess of ethylene glycol is impractical on a large industrial scale, because ethylene glycol is toxic and its high boiling point means that its removal by distillation is energy and time consuming.

Many other processes have been disclosed for the preparation of bosentan, however, they are all multistep processes requiring cumbersome purification processes to obtain the pure product.
U.S. Pat. No. 6,136,971 discloses a process (as shown in Scheme 2) for the preparation of bosentan with high HPLC purity (99.1%) and solves the problem of the dimer formation by utilising a mono-protected 1,2-diheteroethylene anion. In a particularly preferred aspect of the disclosed invention the protecting group is a tert-butyl group used to protect one hydroxyl group of ethylene glycol as an ether. The protecting group is then removed with formic acid to produce a formyloxy-protected ethylene glycol sulfonamide derivative. Treatment of this compound with a base, preferably sodium hydroxide, then produces an ethylene glycol sulfonamide derivative containing a free hydroxy group, namely bosentan.

In view of the above disadvantages associated with the prior art there is a need for an improved process for the preparation of bosentan which is economical and high yielding and which provides bosentan with a high degree of purity.